Susan K. Repertinger

Assessment of HER2 gene status in breast carcinomas with polysomy of chromosome 17

The current study was performed to determine the impact of polysomy 17 on the interpretation of HER2 testing of invasive breast carcinomas using fluorescent in situ hybridization methods. Current American Society of Clinical Oncology/College of American Pathologists guidelines define HER2‐positive tumors as those with >6 HER2 genes per nucleus or those with HER2/CEP17 (chromosome 17) ratio >2.2. These guidelines are potentially contradictory in tumors with polysomy of chromosome 17.

Long survival following bacterial meningitis-associated brain destruction.

This report describes the brain autopsy of a boy who at age 4½ years experienced an episode of fulminant Haemophilus influenzae type b bacterial meningitis, resulting in massive brain destruction and the clinical signs of brain death. However, medical intervention maintained him for an additional two decades. Subsequent autopsy revealed a calcified intracranial spherical structure weighing 750 g and consisting of a calcified shell containing grumous material and cystic spaces with no recognizable neural elements grossly or microscopically. This case represents an example of long survival of brain death with a living body. (J Child Neurol 2006;21:591—595; DOI 10.2310/7010.2006.00137).

The Epidermal Growth Factor Receptor Increases Cytokine Production and Cutaneous Inflammation in Response to Ultraviolet Irradiation

The epidermal growth factor receptor (EGFR) is activated in cutaneous keratinocytes upon ultraviolet (UV) exposure and has been implicated in ultraviolet-(UV-)induced inflammation and skin tumorigenesis. Egfr mutant mice and EGFR inhibitors were used to investigate the hypothesis that EGFR activation augments inflammation following UV irradiation. Topical treatment of mouse skin with the EGFR inhibitor AG1478 before UV exposure suppressed UV-induced erythema, edema, mast cell infiltration, and neutrophil infiltration. Genetic ablation of Egfr and EGFR inhibition by AG1478 also suppressed the increase in the proinflammatory cytokines tumor necrosis factor α (TNF-α), interleukin-1α, KC (murine IL-8), and cyclooxygenase-2 (COX-2) after UV exposure of cultured keratinocytes. Finally, genetic ablation of inhibition of EGFR in cultured keratinocytes decreased p38 activation after UV, while inhibition of p38 kinase reduced COX-2 expression after UV. These data demonstrate that EGFR regulates multiple aspects of UV-induced inflammation and suggest activation of p38 kinase leading to increased COX-2 and cytokine expression as one mechanism through which it acts.

Erbb2 up-regulation of ADAM12 expression accelerates skin cancer progression.

Solar ultraviolet (UV) radiation can cause severe damage to the skin and is the primary cause of most skin cancer. UV radiation causes DNA damage leading to mutations and also activates the Erbb2/HER2 receptor through indirect mechanisms involving reactive oxygen species. We hypothesized that Erbb2 activation accelerates the malignant progression of UV‐induced skin cancer. Following the induction of benign squamous papillomas by UV exposure of v‐rasHa transgenic Tg.AC mice, mice were treated topically with the Erbb2 inhibitor AG825 and tumor progression monitored. AG825 treatment reduced tumor volume, increased tumor regression, and delayed the development of malignant squamous cell carcinoma (SCC). Progression to malignancy was associated with increased Erbb2 and ADAM12 (A Disintegin And Metalloproteinase 12) transcripts and protein, while inhibition of Erbb2 blocked the increase in ADAM12 message upon malignant progression. Similarly, human SCC and SCC cell lines had increased ADAM12 protein and transcripts when compared to normal controls. To determine whether Erbb2 up‐regulation of ADAM12 contributed to malignant progression of skin cancer, Erbb2 expression was modulated in cultured SCC cells using forced over‐expression or siRNA targeting, demonstrating up‐regulation of ADAM12 by Erbb2. Furthermore, ADAM12 transfection or siRNA targeting revealed that ADAM12 increased both the migration and invasion of cutaneous SCC cells. Collectively, these results suggest Erbb2 up‐regulation of ADAM12 as a novel mechanism contributing to the malignant progression of UV‐induced skin cancer. Inhibition of Erbb2/HER2 reduced tumor burden, increased tumor regression, and delayed the progression of benign skin tumors to malignant SCC in UV‐exposed mice. Inhibition of Erbb2 suppressed the increase in metalloproteinase ADAM12 expression in skin tumors, which in turn increased migration and tumor cell invasiveness.

Accelerated elimination of ultraviolet-induced DNA damage through apoptosis in CDC25A-deficient skin.

Cell division cycle 25A (CDC25A) is a dual-specificity phosphatase that removes inhibitory phosphates from cyclin-dependent kinases, allowing cell-cycle progression. Activation of cell-cycle checkpoints following DNA damage results in the degradation of CDC25A, leading to cell-cycle arrest. Ultraviolet (UV) irradiation, which causes most skin cancer, results in both DNA damage and CDC25A degradation. We hypothesized that ablation of CDC25A in the skin would increase cell-cycle arrest following UV irradiation, allowing for improved repair of DNA damage and decreased tumorigenesis. Cdc25a(fl/fl) /Krt14-Cre recombinase mice, with decreased CDC25A in the epithelium of the skin, were generated and exposed to UV. UV-induced DNA damage, in the form of cyclopyrimidine dimers and 8-oxo-deoxyguanosine adducts, was eliminated earlier from CDC25A-deficient epidermis. Surprisingly, loss of CDC25A did not alter epidermal proliferation or cell cycle after UV exposure. However, the UV-induced apoptotic response was prolonged in CDC25A-deficient skin. Double labeling of cleaved caspase-3 and the DNA damage marker γH2A.X revealed many of the apoptotic cells in UV-exposed Cdc25a mutant skin had high levels of DNA damage. Induction of skin tumors by UV irradiation of Cdc25a mutant and control mice on a skin tumor susceptible to v-ras(Ha) Tg.AC mouse background revealed UV-induced papillomas in Cdc25a mutants were significantly smaller than in controls in the first 6 weeks following UV exposure, although there was no difference in tumor multiplicity or incidence. Thus, deletion of Cdc25a increased apoptosis and accelerated the elimination of DNA damage following UV but did not substantially alter cell-cycle regulation or tumorigenesis.

Cervical and endometrial metastases of appendiceal goblet cell carcinoid.

Appendiceal goblet cell carcinoid (GCC) is a rare tumor with histologic features of both adenocarcinoma and neuroendocrine tumor (carcinoid). Clinically, it behaves more aggressively than classic appendiceal carcinoid and commonly presents with peritoneal carcinomatosis. We report 2 cases of appendiceal GCC, one with uterine cervical involvement and the other with endometrial involvement as the initial presentations. The first patients invasive cervical signet ring cell carcinoma was diagnosed on routine screening. The second patient presented with abnormal uterine bleeding, and endometrial curettage showed an adenocarcinoma with signet ring cell features. Primary appendiceal GCC was demonstrated in both cases after systematic clinical investigations. Metastatic appendiceal GCC to uterine cervix and endometrium can potentially be misinterpreted as primary cervical or endometrial signet ring cell carcinoma. Therefore, for any uterine cervical/endometrial signet ring cell carcinoma, a metastatic appendiceal GCC should be considered in the differential diagnosis, especially after excluding other primary sites.

The Epidermal Growth Factor Receptor in Normal and Neoplastic Epithelia

The epidermal growth factor receptor (EGFR) regulates a plethora of cellular and tissue functions in epithelia including cell division, survival, differentiation, and migration. EGFR signaling is up-regulated in pathologies involving aberrant growth like squamous cancer, and facilitates neoplastic progression. Many mechanisms through which the effects of EGFR are modulated in normal and pathological processes have been identified. In particular, recent research has yielded important and surprising insights into the effects of EGFR-dependent signaling on cutaneous biology and carcinogenesis. This review focuses on EGFR signaling in normal biology and squamous cancer, with emphasis on the skin as a model organ to illustrate the biological significance of EGFR signaling.

Mechanisms of SEPA 0009-induced tumorigenesis in v-rasHa transgenic Tg.AC mice

Genetically engineered mouse models with altered oncogene or tumor suppressor gene activity have been utilized recently for carcinogen identification. The v-ras Ha transgenic Tg.AC mouse, with its enhanced susceptibility to skin tumorigenesis, is thought to be well suited for examining the carcinogenicity of topically applied agents. Tg.AC mice were used to examine the carcinogenicity of SEPA 0009, a rationally designed organic molecule designed to enhance drug penetration through the skin. Fifty mg SEPA 0009/kg body weight, 1500 mg SEPA 0009/kg body weight, or the vehicle alone was applied daily to the skin of Tg.AC mice. Nontransgenic FVB/N mice were also treated with the vehicle alone or 1500 mg SEPA 0009. Daily application of a high-dose of SEPA 0009 caused severe and chronic irritation by 1 week that was maintained throughout the experiment. The irritation was accompanied by increased proliferation, increased apoptosis, and expression of the wound-associated keratin 6. High-dose SEPA 0009 induced squamous papillomas in Tg.AC, but not in nontransgenic mice, by 6 weeks. In mice treated with the high dose SEPA 0009, transgene expression was detected in papillomas at week 9, well after the onset of skin irritation and hyperplasia. In contrast, low-dose SEPA 0009 was not irritating to the skin and did not induce papillomas. Thus, SEPA 0009-induced tumorigenesis was associated with chronic and severe irritation. We propose that SEPA 0009-induced tumorigenesis in Tg.AC mice proceeds through an indirect mechanism that is secondary to cutaneous irritation.